Peripheral nerve injuries are common and affect >250,000 individuals annually in the US. Full recovery is rare even after surgical repair; >90% of patients suffer long-term motor and sensory deficits. Functional recovery is poor because peripheral nerves rarely regenerate over long distances. Long-distance regeneration fails largely because Schwann cells lose their ability to support axon regeneration over time after injury. No therapy is currently available to encourage Schwann cells to continue to promote regeneration, and it is not even known whether Schwann cell atrophy can be prevented or reversed. We have recently discovered that induced expression of constitutively active ErbB2 receptor tyrosine kinase (caErbB2) dramatically enhances the regeneration-promoting capability of Schwann cells. Moreover, our preliminary results show that caErbB2 enables chronically denervated, atrophied Schwann cells to enlarge, divide, migrate and extend processes. Notably, we have observed few, if any, effects on innervated Schwann cells that were spared injury, suggesting that therapeutic caErbB2 would have few off-target effects. In this R21 application, we propose to explore further the possibility that caErbB2 reverses Schwann cell atrophy and determine whether it promotes long-distance axon regeneration. We will combine conventional anatomical and functional analyses with advanced techniques such as inducible fluorescent transgenic mice, in vivo imaging and CLARITY, to determine: (1) if induced expression of caErbB2 reactivates atrophied Schwann cells in chronically denervated nerve, and (2) if the Schwann cells reactivated by caErbB2 promote axon regeneration. These proof-of- concept experiments will provide critical data to justify a larger grant application that will investigate the signalin cascades evoked by caErbB2, identify its key effectors, define the therapeutic window of caErbB2 efficacy and develop a therapeutically applicable method of boosting ErbB2 signaling. The proposed work therefore has the potential to establish a strong foundation for developing a potent treatment that enables long- distance nerve regeneration in patients.